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Atopic eczema (AE) is the most common inflammatory skin disease in infancy and its prevalence is rising worldwide. It has a wide social impact on the affected children and their families’ lives. AE can have a chronic and heterogeneous course, with periods of remission and relapse of the clinical manifestations. For this reason, its severity assessment through standardized outcome measures becomes a fundamental guide for health professionals, who can manage AE following evidence-based medicine principles in their everyday clinical practice or in clinical trials.Several scoring systems have been recognized to assess the clinical manifestations of AE, both from the physician’s and the patient’s point of view. Despite the scoring systems standardized for adults, there are very few published options about the expression of a patient/caregiver-centered global severity assessment specifically for pediatric AE. For this reason, the aim of our study was to evaluate a new, quick, user-friendly and feasible caregiver-reported global severity assessment for pediatric AE. Based on a 0–10 numerical rating scale in pediatric AE, we named this scoring system the Comano score.We carried out a cross-sectional observational study enrolling a total of 867 patients aged from 1 to 16 years (males 49.5%, mean patient’s age 5.9 years, standard deviation ±3.6 years) with a previous doctor-confirmed diagnosis of AE, who underwent balneotherapy at Comano Thermal Center (Comano, Trentino, Italy). A strong correlation between Comano score and SCORing Atopic Dermatitis (SCORAD) was observed (r = 0.74, p According to our results, the Comano score may be a promising new tool for the expression of a caregiver-reported global severity assessment in pediatric AE. However, further data are needed to confirm our preliminary findings before health professionals can use this scoring system in their everyday clinical practice to manage pediatric AE. Still, as a patient-focused measure, the Comano score may facilitate delivering person-centered care so as to define a measure for a clinical impact that can be meaningful to the subject, which is gaining importance in modern medicine.

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term referring to various clinical entities, which share the same pathogenetic mechanism. These conditions are caused by somatic gain-of-function mutations in PIK3CA, which encodes the 110-kD catalytic α subunit of PI3K (p110α). These PIK3CA mutations occur as post-zygotic events and lead to a gain of function of PI3K, with consequent constitutional activation of the downstream cascades (e.g., AKT/mTOR pathway), involved in cellular proliferation, survival and growth, as well as in vascular development in the embryonic stage. PIK3CA-related cancers and PROS share almost the same PIK3CA mutational profile, with about 80% of mutations occurring at three hotspots, E542, E545, and H1047. These hotspot mutations show the most potent effect on enzymatic activation of PI3K and consequent downstream biological responses. If present at the germinal level, these gain-of-function mutations would be lethal to the embryo, therefore we only see them in the mosaic state. The common clinical denominator of PROS disorders is that they are sporadic conditions, presenting with congenital or early childhood onset overgrowth with a typical mosaic distribution. However, the severity of PROS is highly variable, ranging from localized and apparently isolate overgrowth to progressive and extensive lipomatous overgrowth associated with life-threatening vascular malformations, as seen in CLOVES syndrome. Traditional therapeutic approaches, such as sclerotherapy and surgical debulking, are often not curative in PROS patients, leading to a recrudescence of the overgrowth in the treated area. Specific attention has been recently paid to molecules that are used and studied in the oncogenic setting and that are targeted on specific alterations of the pathway PI3K/AKT/mTOR. In June 2018, Venot et al. showed the effect of Alpelisib (BYL719), a specific inhibitor for the p110α subunit of PI3K, in patients with PROS disorders who had severe or life-threatening complications and were not sensitive to any other treatment. In these cases, dramatic anatomical and functional improvements occurred in all patients across many types of affected organ. Molecular testing in PROS patients is a crucial step in providing the conclusive diagnosis and then the opportunity for tailored therapy. The somatic nature of this group of diseases makes challenging to reach a molecular diagnosis, requiring deep sequencing methods that have to be performed on DNA extracted from affected tissue. Moreover, even analyzing the DNA extracted from affected tissue there is no guarantee to succeed in detection of the casual somatic mutation, since the affected tissue itself is highly heterogeneous and biopsy approaches can be burdened by incorrect sampling or inadequate tissue sample. We present an 8-year-old girl with CLOVES syndrome, born with a large cystic lymphangioma involving the left hemithorax and flank, multiple lipomas, and hypertrophy of the left foot and leg. She developed severe scoliosis. Many therapeutic approaches have been attempted, including Sildenafil treatment, scleroembolization, laser therapy, and multiple debulking surgeries, but none of these were of benefit to our patient's clinical status. She then started treatment with Rapamycin from May 2019, without significant improvement in both vascular malformation and leg hypertrophy. A high-coverage Whole Exome Sequencing analysis performed on DNA extracted from a skin sample showed a mosaic gain-of-function variant in the PIK3CA gene (p.H1047R, 11% of variant allele frequency). Once molecular confirmation of our clinical suspicion was obtained, after a multidisciplinary evaluation, we decided to discontinue Sirolimus and start targeted therapy with Alpelisib (50 mg/day). We noticed a decrease in fibroadipose overgrowth at the dorsal level, an improvement in in posture and excellent tolerability. The treatment is still ongoing.

Vaccination is a well-known trigger for mast cell degranulation in subjects affected by mastocytosis. Nevertheless, there is no exact standardized protocol to prevent a possible reaction after a vaccine injection, especially for patients who have already presented a previous vaccine-related adverse event, considering that these patients frequently tolerate future vaccine doses. For this reason, we aim to share our experience at Meyer Children’s University Hospital in Florence to raise awareness on the potential risk for future vaccinations and to discuss the valuable therapeutic strategies intended to prevent them, taking into account what is proposed by experts in literature. We describe the case of an 18-month-old female affected by a polymorphic variant of maculopapular cutaneous mastocytosis that presented an extensive bullous cutaneous reaction 24 hours after the second dose (booster dose) of inactivated-tetravalent influenza vaccine, treated with a single dose of oral corticosteroid therapy with betamethasone (0.1 mg/kg) and an oral antihistamine therapy with oxatomide (1 mg/kg/daily) for a week, until resolution. To the best of our knowledge, in the literature, no documented case of reaction to influenza vaccine in maculopapular cutaneous mastocytosis is described. Subsequently, the patient started a background therapy with ketotifen daily (0.05 mg/kg twice daily), a non-competitive H1-antihistamine, and a mast cell stabilizer (dual activity). A non-standardized pharmacological premedication protocol with an H1-receptor antagonist (oxatomide, 0.5 mg/kg) administered 12 hours before the immunizations, and a single dose of betamethasone (0.05 mg/kg) together with another dose of oxatomide (0.5 mg/kg) administered 2 hours before the injections was followed to make it possible for the patient to continue with the scheduled vaccinations. Indeed, no reactions were subsequently reported. Thus, in our experience, a background therapy with ketotifen associated with a premedication protocol made by two doses of oxatomide and a single dose of betamethasone was helpful to make possible the execution of the other vaccines. We suggest how in these children, it could be considered the idea of taking precaution when vaccination is planned, regardless of the kind of vaccine and if a dose of the same vaccine was previously received. However, international consensus needs to be reached to manage vaccinations in children with mastocytosis and previous adverse reactions to vaccines.

Netherton syndrome (NS) is a genetic, multisystemic disease classically distinguished by a triad of clinical manifestations: congenital ichthyosiform erythroderma, hair shaft abnormalities, and immune dysregulation. Due to the complex pathogenesis of the disease, there are no specific therapies currently accessible for patients with NS. An early diagnosis is crucial to start the correct management of these patients. A multidisciplinary approach, including specialists in immunology, allergology, and dermatology, is necessary to set up the best therapeutic pathway. We conducted a review with the aim to summarize the different therapeutic strategies currently accessible and potentially available in the future for children with NS. However, given the limited data in the literature, the best-tailored management should be decided upon the basis of the specific clinical characteristics of the patients with this rare clinical condition. Further comprehension of the pathophysiology of the disease could lead to more efficacious specific therapeutic options, which could allow a change in the natural history of NS.

Background/objectives Nail alterations are commonly seen in cases of idiopathic clubfoot and may cause parental concern. The nature of and whether these changes are congenital or develop secondary to treatment has been poorly investigated. The aim of this study was to evaluate toenail morphology in clubfoot patients at presentation, to re-evaluate them during the course of treatment for the clubfoot, and to analyze findings in the light of the few literature reports for healthy children of the same age. Methods Thirty infants (21 males and 9 females) with idiopathic clubfoot were prospectively enrolled at the Anna Meyer Children's University Hospital. Nails of affected and non-affected feet were evaluated by a team of pediatric dermatologists at presentation and re-evaluated once per patient during the bracing period of Ponseti treatment. Results Toenails of affected (47) and non-affected (13) feet were abnormal at presentation in 43.3% of patients, in both clubfeet (40.4%) and non-affected feet (38.5%), but most changes were physiologic or transitory alterations, commonly found in healthy children, with nail concavity (koilonychia) being the most common finding (29.7%). Changes were not related to clubfoot severity or laterality (P > .05). In most (76.9%) unilateral cases, there was concordance of nail changes between clubfoot and non-affected foot. At re-evaluation (follow-up time 410 ± 207 days), nail problems were more frequent (53.3%); ingrown toenail was the most common (21.6%). Conclusions The presence of nail alterations seems not to be caused by clubfoot pathology and could be related to unfavorable local condition in the brace.

Background Several studies have investigated the efficacy of balneotherapy in atopic dermatitis (AD), including a pediatric open randomized clinical trial conducted at the Comano thermal spring water center, which showed a significant reduction in AD severity and an improvement of the quality of life. However, so far many studies on balneotherapy in pediatric AD have included relatively small populations without identifying patients’ characteristics associated with their response. The aim of the present study was to identify any features associated with the clinical response to the Comano thermal spring water balneotherapy in a large cohort of pediatric AD patients. Methods An observational study was conducted on 867 children aged ≤16 years (females 50.5%, mean patient’s age 5.9 years, standard deviation ±3.6 years) with mild to severe AD who underwent balneotherapy at the Comano thermal spring water center (Comano, Trentino, Italy) from April to October 2014. Patients were stratified according to their disease severity, which was evaluated using five SCORing Atopic Dermatitis (SCORAD) categories before and immediately after a thermal spring water balneotherapy course. Potential characteristics associated with the patients’ clinical response to Comano thermal spring water balneotherapy were investigated. Results A statistically significant improvement in AD severity was observed after Comano thermal spring water balneotherapy (p p p p p Conclusions Comano thermal spring water balneotherapy is a safe complementary treatment for pediatric patients with AD, as it was able to reduce the disease severity, especially in children ≤4 years old, with early onset AD, severe AD or concomitant food allergies.

Background: Gianotti Crosti syndrome (GCS) is a self-healing condition with a spontaneous resolution in 2–6 weeks but, even if rarely, recurrent episodes have been reported.Objective: The aim of this observational study is to investigate serum Immunoglobulin E (IgE) level in children with GCS, evaluating if there is a relationship between IgE level and clinical course of the disease.Methods: Children with GCS diagnosed at a tertiary care children's university hospital between June 2018 and November 2019 were prospectively enrolled. Demographic, clinical and hematochemical data of children investigated were collected. In particular, IgE level were investigated at symptoms onset and, if available, at the following blood tests. Patients were divided in 2 groups on the bases of the clinical course: children with a chronic relapsing course and children who did not present any relapse.Results: Among 29 patients enrolled in this study, 14 (48.3%) children had a chronic relapsing course and 15 (51.7%) did not present any relapse. A statistically significant difference was present considering the length of the disease: 210 days (IQR: 161.25–255) for patients with a chronic relapsing course compared to 40 days (IQR: 30–75) for the other group (p < 0.0001). About the median IgE level in the 2 groups, a value about 10 time higher was found in children with chronic course compared to the other group (1,144 vs. 116 U/mL) with a statistically significant difference (p < 0.0001).Conclusion: Despite the study limitations, a significant correlation between higher IgE levels and chronic-relapsing course of the GCS can be assumed.

Background Propranolol (antagonist of β1-/β2-AR but minimally active against β3-AR) is currently the first-line treatment for infantile hemangiomas (IH). Its efficacy is attributed to the blockade of β2-AR. However, its success rate is ~60%. Considering the growing interest in the angiogenic role of β3-ARs, we evaluated a possible relationship between β3-AR expression and response to propranolol. Methods Fifteen samples of surgical biopsies were collected from patients with IH. Three were taken precociously from infants and then successfully treated with propranolol (responder group). Twelve were taken later, from residual lesions noncompletely responsive to propranolol (nonresponder group). A morphometrical analysis of the percentage of β1-, β2-, and β3-ARs positively stained area was compared between the two groups. Results While no difference was found in both β1- and β2-AR expression level, a statistically significant increase of β3-AR positively stained area was observed in the nonresponder group. Conclusions Although the number of biopsies is insufficient to draw definitive conclusions, and the different β-AR pattern may be theoretically explained by the different timing of samplings, this study suggests a possible correlation between β3-AR expression and the reduced responsiveness to propranolol treatment. This study could pave the way for new therapeutic perspectives to manage IH. Impact Propranolol (unselective antagonist of β1 and β2-ARs) is currently the first-line treatment for IHs, with a success rate of ~60%. Its effectiveness has been attributed to its ability to block β2-ARs. However, β3-ARs (on which propranolol is minimally active) were significantly more expressed in hemangioma biopsies taken from patients nonresponsive to propranolol. This study suggests a possible role of β3-ARs in hemangioma pathogenesis and a possible new therapeutic target.

Background SAPHO (synovitis, acne, pustolosis, hyperostosis and osteitis) syndrome is a rare autoinflammatory chronic disorder, presenting with non-infectious osteitis, sterile joint inflammation and skin manifestations including palmoplantar pustolosis and severe acne. It could be often misdiagnosed for its heterogeneous clinical presentation. Treatment is challenging and, due to the rarity of this syndrome, no randomized controlled clinical trials have been conducted. Empirical treatments, including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibiotics and bisphosphonates and disease-modifying anti-rheumatic drugs (DMARDs) could be quite effective. Anti-tumor necrosis factor-alpha (anti-TNF-α) agents and interleukin-1 (IL-1) antagonists have shown promising results in refractory patients. Isotretinoin, commonly used for severe acne, has been rarely described as possible trigger of osteo-articular manifestations, in particular sacroiliitis. Case presentation The case of a boy, affected by acne fulminans and depression, who presented with sacroiliitis after a 10-week treatment with isotretinoin is presented. After SAPHO diagnosis, NSAIDs therapy was started but the onset of bilateral gluteal hidradenitis suppurativa required the switch to a TNF-α antagonist (Adalimumab) with the achievement of a good control of the disease. Despite specific therapy with sertraline, the patient continued to complains severe depression. Conclusions Our case reports a temporal association between the onset of osteo-articular symptoms and the introduction of isotretinoin, as previously described. However, this timeline is not sufficient to establish a causal role of this drug into the pathogenesis of sacroiliitis. At this regard, further studies are required. The occurrence of hidradenitis suppurativa during SAPHO course supported the introduction of TNF-α blockers with a favourable result, as reported in a few cases in literature. The association between SAPHO syndrome and depressive mood disorders is already reported. Our patient experienced severe depression whose trend seems to be independent from the course of the main disease. Currently, it is not clarified if depression could be considered reactive to the underling disease or if it forms an integral part of the autoinflammatory disorder.

Background SAPHO (synovitis, acne, pustolosis, hyperostosis and osteitis) syndrome is a rare autoinflammatory chronic disorder, presenting with non-infectious inflammatory osteitis, sterile joint inflammation and skin manifestations including palmoplantar pustolosis and severe acne. It could be often misdiagnosed for its heterogeneous clinical presentation. Isotretinoin, which is commonly used for severe acne treatment, has been rarely described as possible trigger of osteo-articular manifestations, in particular sacroiliitis. Various biological treatment have been proposed in refractory patients.Case presentation The case of an adolescent male, affected by acne fulminans and depression, who presented with sacroiliitis after a 10-week treatment with isotretinoin is presented and discussed. After SAPHO diagnosis, the boy started NSAIDs therapy but the onset of bilateral gluteal hidradenitis suppurativa required the switch to a tumour necrosis factor (TNF)-α antagonist (adalimumab). Despite specific therapy with sertraline, the patient continued to complain severe depression, this symptom has been widely reported in patient with SAPHO.Conclusions Our case strengthens the hypothesis that isotretinoin could be a trigger of musculoskeletal involvement in SAPHO. The occurrence of hidradenitis suppurativa as additional clinical feature of SAPHO, already described in literature, supported the TNF-α blocker’s commencement in our patient. Furthermore, the good outcome of our case confirms the efficacy of ADA treatment in obtaining persistent clinical remission of cutaneous and osteoarticular symptoms in SAPHO syndrome.

A 9-year-old girl and her 3-year-old brother were referred with a 15-day history of erythematous annular lesions on their faces (figure 1). Previous treatments with topical steroids had exacerbated the lesion; laboratory findings (full blood count, liver and renal function C-reactive protein) were unremarkable, and no other members of the family had similar skin lesions. Figure 1 Clinical presentation of the fungal infection in the zone of ‘kissing’ contact …

An otherwise healthy 7-year-old girl presented with non-tender, erythematous patches on the left side of her face. The lesions started under the left eye and involved more of the left side of the face with a well demarcated red line on the forehead, nose and the labial mucosa (figure 1). The lesions were non-blanching and were similar to a congenital port-wine stain (PWS) …

Corticosteroids are the mainstay of therapy for many pediatric disorders and sometimes are life-saving. Both endogenous and synthetic derivatives diffuse across the cell membrane and, by binding to their cognate glucocorticoid receptor, modulate a variety of physiological functions, such as glucose metabolism, immune homeostasis, organ development, and the endocrine system. However, despite their proved and known efficacy, corticosteroids show a lot of side effects, among which growth retardation is of particular concern and specific for pediatric age. The aim of this review is to discuss the mechanism of action of corticosteroids, and how their genomic effects have both beneficial and adverse consequences. We will focus on the use of corticosteroids in different pediatric subspecialties and most common diseases, analyzing the most recent evidence.